Question: Audrey T. was tested by a reputable lab two years ago using linkage analysis. She was told she does have the altered VHL gene. She did comprehensive testing, and worried a lot both about herself and about her two adult children and potential grandchildren. Clinical testing revealed only one cyst on the kidney, which is not diagnostic of VHL. Subsequently, the actual alteration in the VHL gene in her family was located, making the direct test available. When her sample was re-tested using direct testing, they found that she does not have the altered gene! While we are thrilled with her results, we are shocked and angry about the two years lived with the wrong information. It raises the question: how many others received false-positive or worse, false-negative results from DNA testing in the past? Should people get re-tested now that the tests have become so much more reliable? -- Lois E., Minnesota

Answer: As we all know, before direct mutation analysis became available, linkage analysis was offered to some families on a research basis and to some on a clinical basis by various centers. Linkage analysis is still used for analysis for some diseases when mutation analysis is not available or has a low rate of mutation detection. I.e., the technique is not obsolete in some circumstances for some diseases. However, for VHL, direct mutation analysis has largely replaced linkage as a preferable test in most cases. Linkage analysis has an inherent misdiagnosis rate for many reasons, that can include crossover events, errors in pedigree structure, incorrect assignment of paternity, low variability of markers, etc. It should be an individual/family decision on who might need retesting, made with the help of a knowledgeable physician or genetic counselor. For some families, all predictions may have already been proven correct and not need retesting.

For those given a normal result, retesting by mutation analysis would certainly be a reasonble option for an added measure of reassurance. It is important to point out that this applies to any lab that did linkage. I am aware of a research lab that gave a misdiagnosis based on linkage as well. Finally , it is important to remember that any lab test can be in error, for e.g. sample mix-up, regardless of the type of test. -- Virginia V. Michels, M.D., Chief, Genetics, Mayo Clinic, Rochester, Minnesota

As printed in the VHL Family Forum 7:1, March 1999. For permission to reprint, please contact VHL Family Alliance, info@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.